Not Applicable
Not Applicable
This invention relates generally to preparing nonracemic chiral alcohols. It more particularly relates to preparing nonracemic chiral alcohols by hydrogenation of ketones using transition metal catalysts comprising nonracemic chiral ligands. Nonracemic chiral alcohols are useful as pharmaceuticals and other bioactive products and as intermediates for the preparation of such products.
Ketones can be converted to racemic chiral alcohols by hydrogenation using certain catalyst systems of ruthenium, a phosphine ligand, a 1,2-diamine, and an alkaline base. Aromatic and heteroaromatic ketones can be hydrogenated to nonracemic chiral alcohols by using certain catalyst systems of ruthenium, an appropriate enantiomeric diphosphine ligand, an enantiomeric 1,2-diamine, and an alkaline base. Angew. Chem. Int. Ed., vol. 40, (2001), 40-73 (a review with 211 references); U.S. Pat. No. 5,763,688; J. Am. Chem. Soc., vol. 117 (1995), 2675-2676; J. Org. Chem., vol. 64 (1999), 2127-2129. Others have noted that such ketones can be hydrogenated to nonracemic chiral alcohols using related catalyst systems formed with a racemic chiral 1,2-diamine. In their catalyst system, the active diastereomeric ruthenium catalyst is formed with the enantiomeric atropisomeric diphosphine ligand and the xe2x80x9cmatchedxe2x80x9d enantiomer of the racemic chiral 1,2-diamine. Interestingly, the diastereomeric ruthenium complex with the xe2x80x9cunmatchedxe2x80x9d enantiomer of the racemic chiral 1,2-diamine, if it is formed, is relatively inactive. Angew. Chem. Int. Ed., vol. 40, (2001), 40-73; European Patent Application 901 997; J. Am. Chem. Soc., vol. 120 (1998), 1086-1087. A catalyst system of ruthenium, the atropisomeric diphosphine (S)-2,2xe2x80x2-bis-(diphenylphosphino)-1,1xe2x80x2-binaphthyl (S-BINAP), achiral ethylene diamine, and potassium hydroxide in isopropanol is reported to hydrogenate 1xe2x80x2-acetonaphthone to (R)-1-(1-naphthyl)-ethanol in 57% enantiomeric excess. The corresponding catalyst system having enantiomeric (S,S)-1,2-diphenylethylenediamine instead of achiral ethylene diamine is reported to hydrogenate 1xe2x80x2-acetonaphthone under the same conditions to (R)-1-(1-naphthyl)ethanol in 97% enantiomeric excess. Angew. Chem. Int. Ed., vol. 40, (2001), 40-73; J. Am. Chem. Soc., vol. 117 (1995), 2675-2676.
An attempt to provide a catalyst system of ruthenium, the atropisomeric diphosphine S-BINAP, enantiomeric (S,S)-1,2-diphenylethylenediamine, and 1,8-diaza-bicyclo[5.4.0]undec-7-ene as the base (in the place of the alkali base used in the references discussed above) gave no catalytic activity for the hydrogenation of acetophenone. The addition of selected alkali salts of tetrakis[3,5-bis(trifluoromethyl)phenyl]borate to this attempted catalyst system provided catalytic activity for the hydrogenation of acetophenone to nonracemic 1-phenethanol. The investigators conclude that alkali metal cations are required for the activity of this catalyst system. Angew. Chem. Int. Ed., vol. 40, (2001), 3581-3585.
The present invention provides a catalyst system as well as a process for the preparation of a nonracemic chiral alcohol by hydrogenation of a ketone using the catalyst system. The catalyst system comprises ruthenium, a nonracemic chiral diphosphine ligand, an amino-thioether ligand, and a base. Surprisingly, and in contrast to teaching in the art, a chiral diamine ligand is not required to obtain highly enantioselective hydrogenation of a ketone to a nonracemic chiral alcohol when using a catalyst system comprising ruthenium, a nonracemic chiral diphosphine ligand, an amine ligand and a base. Accordingly, the present invention provides methods for the highly enantioselective hydrogenation of a ketone to a nonracemic chiral alcohol using an amino-thioether ligand, with a catalyst system also comprising ruthenium, a nonracemic chiral diphosphine ligand, and a base.
In one group of embodiments the base is selected from alkylamidines, alkylguanidines, aminophosphazenes, and proazaphosphatranes.
Not applicable
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
As used herein, the term xe2x80x9ctreatingxe2x80x9d, xe2x80x9ccontactingxe2x80x9d or xe2x80x9creactingxe2x80x9d refers to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product. xe2x80x9cSide-reactionxe2x80x9d is a reaction that does not ultimately lead to a production of a desired product.
xe2x80x9cAlkylxe2x80x9d means a linear saturated monovalent hydrocarbon radical or a branched saturated monovalent hydrocarbon radical or a cyclic saturated monovalent hydrocarbon radical, having the number of carbon atoms indicated in the prefix. For example, (C1-C6)alkyl is meant to include methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl and the like. For each of the definitions herein (e.g., alkyl, alkenyl, alkoxy, aralkyloxy), when a prefix is not included to indicate the number of main chain carbon atoms in an alkyl portion, the radical or portion thereof will have twelve or fewer main chain carbon atoms. A divalent alkyl radical refers to a linear saturated divalent hydrocarbon radical or a branched saturated divalent hydrocarbon radical having the number of carbon atoms indicated in the prefix. For example, a divalent (C1-C6)alkyl is meant to include methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
xe2x80x9cAlkenylxe2x80x9d means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond. For example, (C2-C6)alkenyl is meant to include, ethenyl, propenyl, and the like.
xe2x80x9cAlkynylxe2x80x9d means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond and having the number of carbon atoms indicated in the prefix. For example, (C2-C6)alkynyl is meant to include ethynyl, propynyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d, xe2x80x9caryloxyxe2x80x9d, xe2x80x9caralkyloxyxe2x80x9d, or xe2x80x9cheteroaralkyloxyxe2x80x9d means a radical xe2x80x94OR where R is an alkyl, aryl, aralkyl, or heteroaralkyl respectively, as defined herein, e.g., methoxy, phenoxy, benzyloxy, pyridin-2-ylmethyloxy, and the like.
xe2x80x9cArylxe2x80x9d means a monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms which is substituted independently with one to four substituents, preferably one, two, or three substituents selected from alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino and heteroalkyl. More specifically the term aryl includes, but is not limited to, phenyl, biphenyl, 1-naphthyl, and 2-naphthyl, and the substituted derivatives thereof.
xe2x80x9cAralkylxe2x80x9d refers to a radical wherein an aryl group is attached to an alkyl group, the combination being attached to the remainder of the molecule through the alkyl portion. Examples of aralkyl groups are benzyl, phenylethyl, and the like.
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl radical as defined herein with one, two or three substituents independently selected from cyano, alkoxy, amino, mono- or di-alkylamino, thioalkoxy, and the like, with the understanding that the point of attachment of the heteroalkyl radical to the remainder of the molecule is through a carbon atom of the heteroalkyl radical.
xe2x80x9cHeteroarylxe2x80x9d means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring is optionally substituted independently with one to four substituents, preferably one or two substituents, selected from alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino and heteroalkyl. More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, and the substituted derivatives thereof.
xe2x80x9cHydrocarbylxe2x80x9d is used herein to refer to an organic radical, that can be an alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroalkyl or heteroaryl radical, or a combination thereof which is optionally substituted with one or more substituents generally selected from the groups noted above.
In a general sense, the present invention provides a method for the preparation of a chiral alcohol of formula II (shown without stereochemistry) from a ketone of formula I. Suitable ketones for use in the present invention are those wherein R1 and R2 are different, and optionally, one or both of R1 and R2 have a chiral center. 
The symbols R1 and R2 in formulas I and II each independently represent a hydrocarbyl group that can be an acyclic, cyclic, or heterocyclic hydrocarbyl group, or a combination thereof. Additionally, each of the hydrocarbyl groups R1 and R2 can be saturated or unsaturated, including components defined above as alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkenyl, and alkynyl groups, as well as combinations thereof. Still further, each of R1 and R2 can be optionally substituted with one or more substituents that do not interfere with the reaction chemistry of the invention. In some embodiments, R1 and R2 are linked together in a cyclic structure. In a preferred combination of R1 and R2, R1 is an optionally substituted alkyl group and R2 is an optionally substituted aryl or heteroaryl group.
R1 and R2 can also be, independently, chiral or achiral. As used herein, however, the adjective xe2x80x9cchiralxe2x80x9d in the term xe2x80x9cchiral alcoholxe2x80x9d, specifically refers to the chirality at the carbon atom bearing each of R1 and R2, which chirality is produced by the hydrogenation of the keto group at that center. The term is not meant to refer to the chirality that may be present in either R1 or R2. 
The ruthenium, nonracemic chiral diphosphine ligand, and amino-thioether ligand components of the catalyst system can be provided to the reaction mixture individually to form the reactive catalyst complex in situ or they can be provided as preformed complexes. Preformed complexes of ruthenium with the diphosphine ligand, or the amino-thioether ligand, or both can be used.
Examples of preformed complexes of the ruthenium with the diphosphine ligand include complexes represented by the formula RuX2LYn, wherein X represents a halogen atom or pseudo-halide group, preferably chloride or bromide, L represents the diphosphine ligand, Y represents a weakly coordinating neutral ligand, and n is an integer from 1 to 5. Examples of Y include trialkylamines, for examples triethylamine and tetramethylethylenediamine, and tertiary amides, for example dimethylformamide. Such complexes can be prepared by the reaction of the diphosphine ligand with a complex of the formula [RuX2(arene)]2, wherein examples of the arene include benzene, p-cymene, 1,3,5-trimethylbenzene, and hexamethylbenzene, in a solvent comprising Y.
Examples of preformed complexes of the ruthenium with both the diphosphine ligand and amino-thioether ligand include complexes represented by the formula RuX2LA, wherein A represents the amino-thioether ligand. Such complexes can be prepared by the reaction of the amino-thioether with a complex of the formula RuX2LYn as described above.
The ruthenium component of the catalyst system, whether provided to the reaction mixture separately from the other components or used to form a preformed complex with the diphosphine ligand, the amino-thioether ligand, or both, can be provided by any ruthenium salt or complex capable of forming the active catalyst system in combination with the diphosphine ligand, the amino-thioether ligand, and the base. This can be determined by routine functional testing for ketone hydrogenation activity and enantioselectivity in the manner shown in the Examples. A preferred source of the ruthenium component is a complex of the formula [RuX2(arene)]2 as defined above.
Suitable nonracemic chiral diphosphine ligands for the present invention are bis-tertiary phosphines of the general formula R3R4PRaPR5R6, wherein R3, R4, R5, and R6 are hydrocarbyl radicals, which may be the same or different, and Ra is a hydrocarbyl diradical, any of which may be optionally linked in one or more cyclic structures. Suitable hydrocarbyl groups R3, R4, R5, R6, and diradicals thereof for Ra, include acyclic, cyclic, or heterocyclic hydrocarbyl groups, or combinations thereof. Additionally, each of the hydrocarbyl groups R3, R4, R5, R6 and Ra can be saturated or unsaturated, including components defined above as alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkenyl, and alkynyl groups, as well as combinations thereof. Still further, each of R3, R4, R5, R6 and Ra can can be optionally substituted with one or more substituents that do not undesirably affect the reaction chemistry of the invention.
The chirality of the diphosphine ligand may reside in one or more of the hydrocarbyl groups R3, R4, R5, R6, in the bridging hydrocarbyl radical Ra, at phosphorus when two hydrocarbyl radicals on phosphorus are different (R3xe2x89xa0R4, or R5xe2x89xa0R6, or both), or combinations thereof. Chirality in the bridging hydrocarbyl diradical Ra may be due to the presence of one or more stereogenic carbon atoms or due to atropoisomerism.
Illustrative examples of nonracemic chiral diphosphines are the enantiomers of 2,2xe2x80x2-bis(diphenyl-phosphino)-1,1xe2x80x2-binaphthyl (BINAP), BINAP derivatives having one or more alkyl groups or aryl groups connected to one or both naphthyl rings, BINAP derivatives having 1-5 alkyl substituents on the phenyl rings bonded to phosphorus, for example 2,2xe2x80x2-bis-(di-p-tolylphosphino)-1,1xe2x80x2-binaphthyl (TolBINAP), 5,6,7,8,5xe2x80x2,6xe2x80x2,7xe2x80x2,8xe2x80x2-octahydro-BINAP (H8BINAP), 2,2xe2x80x2-bis(dicyclohexylphosphino)-6,6xe2x80x2-dimethyl-1,1xe2x80x2-biphenyl (BICHEP), 2,2xe2x80x2-bis(diphenylphosphino)-6,6xe2x80x2-dimethoxy-1,1xe2x80x2-biphenyl (MeOBIPHEP), 1-[1,2-bis-(diphenylphosphino)ferrocenyl]ethyldimethylamine (BPPFA), 2,3-bis(diphenyl-phosphino)butane (CHIRAPHOS), 1-cyclohexyl-1,2-bis(diphenylphosphino)ethane (CYCPHOS), 1-substituted 3,4-bis(diphenyl-phosphino)pyrolidine (DEGPHOS), 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane (DIOP), 1,2-bis[(o-methoxyphenyl)phenylphosphino]ethane (DIPAMP), 2,5-disubstituted 1,2-bis(phospholano)benzenes (DuPHOS), for example 1,2-bis(2,5-dimethylphospholano)-benzene (Me-DuPHOS), substituted 1,2-bis(phospholano)ethylenes (BPE), for example 1,2-bis(2,5-dimethylphospholano)ethylene (Me-BPE), 5,6-bis(diphenylphosphino)-2-norbornene (NORPHOS), N,Nxe2x80x2-bis-(diphenylphosphino)-N,Nxe2x80x2-bis(1-phenylethyl)ethylene-diamine (PNNP), 1,2-bis-(diphenylphosphino)propane (PROPHOS), 2,4-bis(diphenyl-phosphino)pentane (SKEWPHOS), [6,7,8,9-tetrahydro-dibenzo[b,d]-[1,6]-dioxecin-1,14-diyl]-bis(diphenylphosphine) (C4-TunaPhos), 3,4-O-isopropylidene-3,4-dihydroxy-2,5-bis-(diphenylphosphino)hexane (DIOP*), 1,2-bis {4,5-dihydro-3H-dinaphtho-[2, 1-c: 1xe2x80x2,2xe2x80x2-e]-phosphino}benzene (BINAPHANE), 1,1xe2x80x2-bis-{4,5-dihydro-3H-dinaphtho[2,1-c: 1xe2x80x2,2xe2x80x2-e]-phosphino}ferrocene (f-BINAPHANE), 1,2-bis-[3,4-O-isopropylidene-3,4-dihydroxy-2,5-dimethylphospholanyl]benzene (Me-KetalPhos), 1,1xe2x80x2-bis[3,4-O-isopropylidene-3,4-dihydroxy-2,5-dimethyl-phospholanyl]ferrocene (Me-f-KetalPhos), 2,2xe2x80x2-bis(diphenyl-phosphino)-1,1xe2x80x2-dicyclopentane (BICP), 1,2-bis-{2,5-disubstituted-7-phosphabicyclo[2.2.1]-hept-7-yl}benzenes (PennPhos), for example 1,2-bis-{2,5-dimethyl-7-phosphabicyclo[2.2.1]-hept-7-yl}benzene (Me-PennPhos) and 1,2-bis-{2,5-diisopropyl-7-phosphabicyclo[2.2.1]-hept-7-yl}benzene (iPr-PennPhos), and 1,2-bis {1-phosphatricyclo[3.3.0.0]undecan-1-yl}-benzene (C5-Tricyclophos), and equivalents thereto that are recognized by those skilled in the art.
Preferred nonracemic diphosphine ligands comprise a 2,2xe2x80x2-bis-(diorgano-phosphino)-1,1xe2x80x2-bis(cyclic) structure, wherein each cycle of the bis(cyclic) structure comprises three to eight carbon atoms, and wherein the 1, 1xe2x80x2, 2, and 2xe2x80x2 carbon atoms in the bis(cyclic) structure are saturated. These ligands are described in detail in U.S. Pat. No. 6,037,500, incorporated herein by reference. The preferred nonracemic diphosphine ligands comprising a 2,2xe2x80x2-bis-(diorgano-phosphino)-1,1xe2x80x2-bis(cyclic) structure are of the formulas III and IV and their enantiomers, in which m=1 to 6 and wherein each cycle of the bis(cyclic) structure may be unsubstituted as shown in formulas III and IV or further substituted with one or more substituents chosen from hydrocarbyl substituents and heteroatom containing substituents that do not interfere with the ketone hydrogenation chemistry, and wherein Rxe2x80x2 is a substituted or unsubstituted hydrocarbyl group selected from alkyl groups and aryl groups. 
Particularly preferred nonracemic diphosphine ligands are of the formula V and its enantiomer, wherein Ar is an aryl group. 
Preferred aryl groups in formula V are phenyl (the BICP ligand) and mono-, di-, and trialkyl-phenyl, particularly wherein alkyl is methyl, for example 2,2xe2x80x2-bis[di(3,5-dimethylphenyl)phosphino]-1,1xe2x80x2-dicyclopentane (3,5-Me8BICP).
Suitable amino-thioether ligands for the present invention are of the general formula H2NRcSR7, wherein R7 is a hydrocarbyl radical and Rc is a hydrocarbyl diradical and which may be optionally linked in a cyclic structure. Suitable hydrocarbyl groups R7 and diradicals thereof for Rc include acyclic, cyclic, and heterocyclic hydrocarbyl groups, include saturated and unsaturated hydrocarbyl groups, include alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkenyl, and alkynyl groups, and can be optionally substituted with one or more substituents that do not undesirably the reaction chemistry of the invention. The amino-thioether ligand may be achiral, racemic chiral, or nonracemic chiral, preferably achiral.
Preferred amino-thioether ligands are selected from 2-(alkylthio)ethylamines, 2-(alkylthio)anilines, and equivalents thereto that are recognized by those skilled in the art. Most preferred are 2-(alkylthio)anilines. Preferably the alkyl group therein is selected from C1 to C4 alkyl groups. Most preferred are methyl and ethyl. Illustrative examples include 2-(methylthio)aniline and 2-(ethylthio)aniline.
Suitable bases include basic inorganic and organic salts, preferably selected from basic salts comprising a cation selected from an alkali metal cation, an alkaline earth cation, and quaternary ammonium cation and a basic anion selected from hydroxide and alkoxide anions. Examples include lithium, sodium, potassium, and quaternary ammonium salts of hydroxide, methoxide, ethoxide, isopropoxide, and t-butoxide.
In a further inventive embodiment of the invention, the base is selected from alkylguanidines, aminophosphazenes, proazaphosphatranes, and alkylamidines. In this embodiment, the base is preferably selected from alkylguanidines, aminophosphazenes, and proazaphosphatranes. In this embodiment, the base is most preferably selected from alkylguanidines.
Suitable alkylguanidines have the general formula VI, wherein R8, R9, R10, R11, and R12 are independently selected from hydrogen and alkyl groups, with the proviso that at least one of R8, R9, R10, R11, and R12 is an alkyl group. 
Preferably the alkylguanidine comprises two alkyl groups, more preferably three alkyl groups, even more preferably four alkyl groups, and most preferably five alkyl groups. Any of the alkyl groups R8, R9, R10, R11, and R12 may be optionally linked in one or more cyclic structures. An illustrative example of a suitable tetraalkylguanidine base is 1,5,7-triazabicyclo[4.4.0]dec-5-ene and tetramethylguanidine. Illustrative examples of suitable pentalkylguanidines are 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene and tetramethyl-2-t-butylguanidine.
Suitable aminophosphazenes have the general formula VII, wherein R13 is selected from hydrogen and alkyl groups, R14 is an alkyl group and the two R14 groups on each xe2x80x94NR142 group may optionally be linked in a cyclic structure, and x is an integer from zero to three.
R13Nxe2x95x90P(xe2x80x94NR142)x[xe2x80x94Nxe2x95x90P(NR142)3](3-x)xe2x80x83xe2x80x83VII
Illustrative examples of suitable aminophosphazenes include N,N,Nxe2x80x2,Nxe2x80x2,Nxe2x80x3,Nxe2x80x3-hexa-methyl-phosphorimidic triamide (R13xe2x95x90H, R14=methyl, x=3), Nxe2x80x2xe2x80x3-t-butyl-N,N,Nxe2x80x2,Nxe2x80x2,Nxe2x80x3,Nxe2x80x3-hexamethyl-phosphorimidic triamide (R13=t-butyl, R14=methyl, x=3), (t-butyl-imino)-tris(pyrrolidino)-phosphorane (R13=t-butyl, xe2x80x94NR142=pyrrolidino, x=3), Nxe2x80x2xe2x80x3-[N-ethyl-P,P-bis-(dimethyl-amino)phosphinimyl]-N,N,Nxe2x80x2,Nxe2x80x2,Nxe2x80x3,Nxe2x80x3-hexamethyl-phosphorimidic triamide (R13=ethyl, R14=methyl, x=2), and t-butyl-tris[tris(dimethyl-amino)-phosphoranylidene]phosphorimidic triamide (R13=t-butyl, R14=methyl, x=0).
Suitable proazaphosphatranes are described in U.S. Pat. No. 5,051,533 and have the general formula VIII, wherein R15, R16, and R17 are independently selected from hydrogen and alkyl groups. 
Preferably R15, R16, and R17 are selected from C1 to C8 alkyl groups, most preferably methyl. An illustrative preferred proazaphosphatrane is 2,8,9-trimethyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (R15xe2x95x90R16=R17=methyl).
Suitable alkylamidines have the general formula IX wherein R18, R19, and R20 are independently selected from alkyl groups and R21 is selected from hydrogen and alkyl groups. Preferably, R21 is selected from alkyl groups. 
Any of the alkyl groups R18, R19, R20, and R21 may be optionally linked in one or more cyclic structures. An illustrative example of a suitable alkylamidine base is 1,5-diazabicyclo[4.3.0]non-5-ene.
The components of the catalyst system are each present in catalytic amounts, meaning less than stoichiometric relative to the ketone reactants. The minimum amount of the catalyst system relative to the ketone reactant may depend on the activity of the specific catalyst system composition, the specific ketone to be reacted, the hydrogen pressure, the gas-liquid mixing characteristics of the reaction vessel, the reaction temperature, the concentrations of the reactants and catalyst system components in the solution, and the maximum time allowed for completion of the reaction, and can be readily determined by routine experimentation. In typical embodiments, the mole ratio of the ruthenium component of the catalyst system to the ketone reactant is in the range from about 1/100 to about 1/100,000, preferably in the range from about 1/500 to about 1/10,000.
The mole ratio of the nonracemic diphosphine ligand to the ruthenium in the catalyst system is typically in the range from about 0.5 to about 2.0, preferably from about 0.8 to about 1.2, and most preferably is about 1. The mole ratio of the amino-thioether ligand to the ruthenium in the catalyst system is typically in the range from about 1 to about 50, and preferably from about 5 to about 20. The mole ratio of the base to the ruthenium in the catalyst system is typically in the range from about 1 to about 100, and preferably from about 5 to about 50.
The hydrogenation reaction may be conducted without solvent when the ketone itself is a liquid at the reaction temperature and capable of dissolving the catalyst system. More typically, the hydrogenation reaction is conducted in a solvent system that is capable of dissolving the catalyst system and is reaction-inert. The term solvent system is used to indicate that a single solvent or a mixture of two or more solvents can be used. The term reaction-inert it used to mean that the solvent system does not react unfavorably with the reactants, products, or the catalyst system. It does not mean that the solvent does not participate productively in the desired reaction. For example, while not wishing to be bound by theory, it is believed that when the base is selected from alkylguanidines, aminophos-phazenes, or proazaphosphatranes and the solvent is selected from alcohol solvents, the alcohol solvent levels the base. That is, these bases deprotonate the alcohol to form an alkoxide base in the reaction solution.
The solvent system need not bring about complete solution of the ketone reactant or the chiral alcohol product. The ketone reactant may be incompletely dissolved at the beginning of the reaction or the chiral alcohol product may be incompletely dissolved at the end of the reaction, or both.
Representative solvents are aromatic hydrocarbons such as benzene, toluene, xylene; aliphatic hydrocarbons such as pentane, hexane, heptane; halogen-containing hydrocarbon solvents such as dichloromethane and chlorobenzene; alkyl ethers, polyethers, and cyclic ethers such as methyl-t-butyl-ether, dibutylether, diethoxymethane, 1,2-dimethoxyethane, and tetrahydrofuran; ester solvents such as ethyl acetate, organic solvents containing heteroatoms such as acetonitrile, DMF and DMSO; and alcohol solvents such as methanol, ethanol, 2-propanol, t-butanol, benzyl alcohol and the like; and mixtures thereof. Preferably, the solvent system comprises an alcohol solvent. Most preferably, the alcohol solvent is 2-propanol.
In typical embodiments, the reaction is suitably conducted at a temperature from about xe2x88x9230xc2x0 C. to about 100xc2x0 C., more typically from about 0xc2x0 C. to about 50xc2x0 C., and most typically from about 20xc2x0 C. to about 40xc2x0 C.
The terms xe2x80x9chydrogenatingxe2x80x9d and xe2x80x9chydrogenationxe2x80x9d refer to reacting the ketone with a source of hydrogen atoms under appropriate conditions so that two hydrogen atoms are added to the carbonyl group of the ketone to produce the hydroxyl group of the chiral alcohol. The source of hydrogen atoms may be molecular hydrogen (H2), a hydrogen donating organic or inorganic compound, or mixtures thereof. Preferably the source of hydrogen atoms includes molecular hydrogen. Hydrogen donating compounds are compounds capable of donating hydrogen atoms via the action of the catalyst system. Compounds capable of donating hydrogen atoms for transfer hydrogenation reactions using ruthenium catalysts are known in the art, and include alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol and benzyl alcohol, formic acid and salts thereof, unsaturated hydrocarbons and heterocyclic compounds having in part a saturated Cxe2x80x94C bond such as tetralin, cyclohexane, and cyclohexadiene, hydroquinone, phosphorous acid, and the like. Among hydrogen donating compounds, alcohols are preferred and isopropanol is most preferred.
The hydrogen pressure in the reaction is typically at least about 1 atm, and typically in the range from about 1 atm to about 100 atm. More typically, the hydrogen pressure is in the range from about 5 atm to about 20 atm.
The reaction rate and time to completion are dependent on the identities of the ketone reactant and the catalyst components, their absolute concentrations and relative ratios, the temperature, the hydrogen pressure, the gas-liquid mixing provided, and the other reaction conditions. Typically, the reaction is allowed to continue for sufficient time to complete the conversion of the ketone reactant. For typical ketone reactants, using the preferred catalyst systems described and the preferred reaction conditions described herein, the reaction is typically completed in a period of time in the range from about a few minutes to about 24 hours, more typically in the range from about 1 hour to about 10 hours.
The nonracemic chiral alcohol product has, by definition, a stereomeric excess greater than zero. In preferred embodiments, the nonracemic chiral alcohol is formed in at least about 50% stereomeric excess, more preferably at least about 60%, still more preferably at least about 70%, still again more preferably at least about 80%, and most preferably at least about 90%. These stereomeric excesses refer to the chirality at the hydroxyl-bearing carbon of the alcohol group generated by the hydrogenation of the ketone group. When the ketone is achiral, the chiral alcohol can be one of two enantiomers, and the enantiomer excess (e.e.) is the measure of stereomeric excess. When the ketone reactant is already chiral, the chiral alcohol product is a diastereomer, and diastereomeric excess (d.e.) is the formally appropriate measure of stereomeric excess. Accordingly, the term xe2x80x9cnonracemic diastereomerxe2x80x9d when used to refer to a nonracemic chiral alcohol product, refers to a product with an excess of one diastereomer vs. its diastereomer with the opposite chirality at the hydroxyl-bearing carbon. Preferably, the nonracemic diastereomer is produced in at least about 50% d.e., more preferably at least about 60% d.e., still more preferably at least about 70% d.e., still again more preferably at least about 80% d.e., and most preferably at least about 90% d.e.